A Dose-Finding and Efficacy Study of Venetoclax, CC-486, and Obinutuzumab in Follicular Lymphoma

INCLUSION CRITERIA Participants are eligible to be included in the study if all of the following criteria apply: 1. Male and female participants who are at least 18 years old with a medically confirmed diagnosis of grade 1-3a follicular lymphoma by 2017 World Health Organization criteria. A prior tissue or bone marrow biopsy may be used to confirm diagnosis if collected within 90 days of initiating therapy. 2. Treatment-naive (you have never had treatment for your cancer) or if you have received treatment, you have received fewer than two prior lines of anti-CD20 monotherapy consisting of a total of 16 or fewer doses. 3. Must have Stage II-IV disease on screening PET imaging with measurable disease, according to Lugano Classification. Measurable disease will be defined as at least one lesion that can be accurately measured in at least two dimensions and quantifiable avidity ( a tumor containing antibodies that have a higher rate/stability of binding with an antigen) to F-fluorodeoxyglucose (also known as "FDG" - a glucose analogue that can be high in cancerous tumors) . Minimum measurement must be \>15 mm in the longest diameter by \>10 mm in the short axis. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less as defined in Appendix B. Performance status must be evaluated within 28 days prior to treatment initiation. 5. There must be a clear way to indicate that you need treatment, either by meeting one or more of the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria for treatment (Brice et al. 1997), the existence of cancer-related pain or other uncontrollable symptoms. Study participant whose need for treatment can be supported by the judgment of a primary oncologist based on the pace of their disease progression/other clinical criteria are also eligible for the study. Study participants must have documented progression of disease. 6. Not be a candidate for standard-of-care chemoimmunotherapy in the judgment of the primary oncologist OR standard chemoimmunotherapy was discussed with the primary oncologist and declined by the participant. 7. A male participant must agree to use contraception during the treatment period of this study, and for at least 90 days after the last dose of venetoclax or 18 months after the last dose of obinutuzumab, whichever is longer, and refrain from donating sperm during this period. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after the last dose of obinutuzumab to avoid exposing the embryo. 8. A female participant is eligible to participate if she is not pregnant, breastfeeding, and at least one of the following conditions applies: * She is not a woman of childbearing potential * She is a woman of childbearing potential who agrees to follow the contraceptive guidance during the treatment period and for at least 30 days after the last dose of venetoclax or 18 months after the last dose of obinutuzumab, whichever is longer. * Participants must have a negative pregnancy test within 72 hours of beginning treatment if they are women of childbearing potential. 9. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. 10. Have adequate organ function that can be confirmed by clinical laboratory values within 28 days prior to treatment initiation. EXCLUSION CRITERIA Participants are excluded from the study if any of the following criteria apply: 1. A a woman of childbearing potential who has a positive urine pregnancy test within 72 hours prior to treatment allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: In the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for the subject to start receiving study medication. 2. Has received any prior systemic therapy other than anti-CD20 monoclonal antibody or radiotherapy prior to the first dose of study medication. Subjects must not have had a prior dose of anti-CD20 monoclonal antibody therapy within 28 days prior to the first dose of study medication. 3. Known hypersensitivity or allergy to any of the study drugs, xanthine oxidase inhibitors and/or rasburicase, mannitol, murine products, or any components of the drug formulations. 4. History of severe allergic or anaphylactic reaction to humanized or murine monoclonal antibodies. 5. History of other malignancy that could affect compliance with the study or interpretation of results such as: * Participants with a history of basal or squamous cell carcinoma or stage 1 melanoma of the skin or in situ carcinoma of the cervix are eligible. * Participants with a malignancy that has been treated with surgery alone with the intent to cure the participant will also be excluded. Individuals in documented remission without treatment for 2 years prior to enrollment may be included at the discretion of the doctor leading the study. 6. Has medical/clinical evidence of transformation to an aggressive lymphoma subtype including grade 3b Follicular Lymphoma. 7. Has received the following agents within 7 days prior to the first dose of venetoclax: * Steroid therapy for anti-neoplastic intent * A strong or moderate Cytochrome P450 3A (abbreviated as "CYP3A" inhibitor). * CYP3A inducers * Consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax * P-glycoprotein (P-gp) inhibitors or narrow therapeutic index P-gp substrates 8. Evidence of significant, uncontrolled diseases that could affect the participant's ability to fulfill their role in the study/ protocol or interpretation of results or that could increase risk to the participant, including renal disease that would preclude chemotherapy administration or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm). 9. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1. Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment) will result in study exclusion. Caution should be exercised when considering the use of any of the study medication in participants with a history of recurring or chronic infections. 10. Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis. 11. Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) antibody. Participants who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation. Participants with occult or prior HBV infection (defined as positive total hepatitis B core antibody \[HBcAb\] and negative HBsAg) may be included if HBV DNA is undetectable. These participants must be willing to undergo monthly HBV DNA testing. 12. Receipt of live-virus vaccines within 30 days prior to the initiation of study treatment 13. Malabsorption syndrome, inability to swallow a large number of pills, or other condition that precludes enteral route of administration. 14. A history of progressive multifocal leukoencephalopathy (PML) or known prior infection with the John Cunningham (JC) virus. 15. Significant active cardiac disease within the previous 6 months including New York Heart Association class 4 heart failure, unstable angina, or myocardial infarction.